Combination of IAP inhibitors with PARP or MEK inhibitors or other chemotherapeutic agents

A technology of inhibitors and compositions, applied in the direction of drug combination, organic chemistry, anti-toxic agent, etc.

Pending Publication Date: 2021-06-18
ASCENTAGE PHARMA SUZHOU CO LTD +1
View PDF6 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Despite the many treatment options for cancer patients, there is still a need for effective and safe molecularly targeted anticancer agents

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Combination of IAP inhibitors with PARP or MEK inhibitors or other chemotherapeutic agents
  • Combination of IAP inhibitors with PARP or MEK inhibitors or other chemotherapeutic agents
  • Combination of IAP inhibitors with PARP or MEK inhibitors or other chemotherapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0221] abbreviation

[0222]

[0223]

[0224]

[0225] compound synthesis

[0226] The preparation of the IAP inhibitors of the present invention is disclosed in International Patent Published Application No. WO2014 / 031487, which is incorporated herein by reference in its entirety.

example 1

[0228] animal:

[0229] Balb / c nude mice, female, 4-6 weeks old, weighing about 18-22 g, were purchased from GemPharmatech Co., Ltd (Nanjing, Jiangsu).

[0230] Biogenesis of Xenograft (PA1170, PA6265, PA0787, and PA1194) Models Derived from Subcutaneous Pancreatic Cancer Patients to make:

[0231] All PDX models were initially established from surgically resected clinical samples (cancer type: pancreatic adenocarcinoma) and implanted into nude mice defined as passage 0 (P0). The next passage from P0 tumor implantation was defined as passage 1 (P1), and so on during serial implantation of mice. Frozen tumor fragments were revived in NOD SCID mice, and when tumors had grown to an appropriate size, they were passaged to Balb / c nude mice. P4-P7 tumors were used for research. Complete exome sequencing and RNA sequencing revealed BRCA2, CDKN2A, and KRAS mutations in PA1170; BRCA1, KRAS, and TP53 mutations in PA6265; CDKN2A, KRAS, and TP53 mutations in PA0787; and KRAS and ...

example 24

[0267] The antitumor activity of the compound of Example 24 plus olaparib in PDX model PA6265 of pancreatic cancer carrying BRCA1 mutation is shown in image 3 and Table 4, olaparib was moderately active on tumor growth at 50 mg / kg (p.o. BID for 4 weeks), with a T / C value of 72% at day 28 (P Figure 4 As shown, there was no significant change in body weight during all treatment periods in PA7265.

[0268] Table 4 RTV, RTV, T / C (%) value and synergy score at key time points in PA6265

[0269]

[0270]

[0271] Taken together, these results indicate that the combination therapy of the compound of Example 24 and olaparib achieves a synergistic effect and further enhances the anti-tumor effect in tumors carrying BRCA1 or BRCA2 mutations.

[0272] B. The compound of Example 24 improves the antitumor activity of trametinib in a pancreatic PDX model.

[0273] The compound of Example 24 was tested in combination with Trametinib in xenograft models PA1170 and PA6265 derived from ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to a pharmaceutical composition. The pharmaceutical composition comprises a) an effective amount of an apoptosis inhibitor protein (IAP) inhibitor, wherein the IAP inhibitor is represented by the formula (I): or a pharmaceutically acceptable salt thereof, and the definition of each variable is provided herein; B) an effective amount of a second inhibitor, wherein the second inhibitor is a poly ADP ribose polymerase (PARP) inhibitor or a mitogen-activated protein kinase (MEK) inhibitor; and a pharmaceutically acceptable carrier or diluent.

Description

technical field [0001] The present invention relates to combination therapy of bivalent inhibitors of apoptosis inhibitory protein (IAP) and poly ADP ribose polymerase (PARP) inhibitors or mitogen activated protein kinase kinase (MEK) inhibitors or other chemotherapeutic agents. Background technique [0002] Apoptosis, or programmed cell death, is a cellular process critical for homeostasis, normal development, host defense, and tumorigenesis suppression. Misregulation of apoptosis has been implicated in many human diseases, (1) including cancer, (1),(3) And it is now recognized that resistance to apoptosis is a hallmark of cancer. (4) Therefore, targeting of key apoptosis regulators has become an attractive strategy for developing new approaches to human cancer therapy. (1) [0003] Most current cancer therapies, including chemotherapeutics, radiation and immunotherapy, indirectly induce apoptosis in cancer cells. Thus, the inability of cancer cells to execute the apop...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/407A61K31/502A61K31/519A61K31/337A61K31/7068A61P35/00A61P1/18A61P1/04A61P3/10A61P7/06A61P1/16A61P29/00A61P1/12A61P1/00A61P17/06A61P19/02A61P17/00A61P21/04A61P21/00A61P37/06A61P39/00
CPCA61K45/06A61K31/407A61K31/502A61K31/519A61K31/337A61K31/7068A61P35/00A61P1/18A61P1/04A61P3/10A61P7/06A61P1/16A61P29/00A61P1/12A61P1/00A61P17/06A61P19/02A61P17/00A61P21/04A61P21/00A61P37/06A61P39/00A61K2300/00C07D487/04A61K31/5545C07D519/00
Inventor 翟一帆杨大俊方东李强
Owner ASCENTAGE PHARMA SUZHOU CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap